Herpes stromal keratitis (HSK) remains the leading infectious cause of blindness in the United States. Evidence from mouse models of HSK suggest that the inflammation is mediated preferentially by CD4+ T cells in part through the production of Th1 cytokines (IFN-? and IL-2). However, basic components of this immunoinflammatory process remain poorly defined and controversial. For instance, the relative contribution of HSV- specific and bystander activated CD4+ T cells to HSK remains uncertain, as does the requirements for their activation. Although dendritic cells (DC) have been strongly implicated in HSK, several issues require clarification, including: delineation of the timing of their involvement;the DC subpopulations involved;and the relative contribution of local DCs and infiltrating DCs from the blood. Moreover, although Th1-, and Th2- differentiated CD4+ T cells have been implicated in the positive and negative regulation of HSK, respectively;a role for the recently defined Th17 subpopulation of CD4+ T cells is unexplored, but suggested by the presence of IL-17 in corneas with HSK. We propose to use well-characterized HSV-specific Th1 and Th17 CD4+ T cell clones we have isolated from corneas with HSK along with OVA-specific CD4+ T cells to investigate the contribution of HSV-specific and bystander activated CD4+ T cells to HSK severity (Specific Aim 1). We will also utilize knock-in mice that express the diphtheria toxin receptor from CD11c promoter expressed in all DC, or from the Langerin promoter expressed only in Langerhans cells, as well as mice that are constitutively deficient in Langerhans cells to investigate the contribution of DC subpopulations to various stages of HSK development and progression (Specific Aim 2). Our studies will address these issues of fundamental importance to HSK at a level of sophistication made possible by reagents that are uniquely available in our laboratory. Herpes stromal keratitis (HSK) results from herpes simplex virus type 1 (HSV-1) infection of the cornea, and is a leading cause of blindness. Because HSK is an immunopathological process, our goal is to understand the underlying immunological mechanisms, and use this information in the design of immunology-based therapeutic intervention. Effective therapy for HSK would significantly reduce visual impairment, increase productivity of the American worker, and reduce the heavy burden of treating HSK on the American health care system.